The Branch has a long-standing involvement in the systematic evaluation of radiotherapy alone or in combination with chemotherapeutic drugs. As more individuals become long-term cancer survivors, there is greater need to evaluate risk-benefit ratios for various treatment protocols. Secondary Breast Cancer following Hodgkin's DiseaseTo quantify the long-term risk of breast cancer associated with use of radiotherapy and chemotherapy to treat young women with HD, a case-control study of breast cancer was conducted within a cohort of 3817 female 1-year survivors of HD diagnosed at age 30 years or younger. A radiation dose of 4Gy or more delivered to the breast was associated with a 3.2 fold (95% confidence interval [CI], 1.4-8.2) increased risk, compared with the risk in patients who received lower doses and no alkylating agents. Risk increased to 8-fold (95% CI, 2.6-26.4) with a dose of more than 40Gy (P less than .001 for trend). Risk of breast cancer decreased with increasing number of alkylating agent cycles (P=.003 for trend). Risk was also low (RR, 0.4; 95% CI, 0.1-1.1) among women who received 5 Gy or more delivered to ovaries compared with those who received lower doses. Additional analyses are underway.Second Cancer Risks following RetinoblastomaLong-term follow-up of a cohort of 1,600 Retinoblastoma (RB) patients revealed a statistically significant excess of leiomyosarcomas in herediatary RB patients 30 years and later after treatment for RB. RB patients who have developed melanoma are undergoing clinical examination for dysplastic nevi syndrome, lipomas, and mutations in melanoma susceptibility genes. DNA collected from hereditary RB patients with a second cancer are being genotyped to identify mutations in the RB1 gene that increase susceptibility to a second cancer. Cancer Risks in Family Members of Ataxia-Telangiectasia PatientsAn international workshop organized by NCI was held with investigatorsfrom the UK, France and four Nordic countries to discuss pooling data to investigate cancer incidence in family members of ataxia-telangiectasia patients.Cancer Mortality and Incidence Risks in Patients with ScoliosisA multi-center retrospective cohort study of 5,573 women who were monitored with diagnostic x-rays for their scoliosis found that they were 70% more likely to die from breast cancer than women in the general population. A statistically significant linear dose-response relationship was observed, with an excess relative risk per Gy of 5.4. We recently completed an analysis of breast cancer incidence among scoliosis patients and submitted a manuscript for publication. Analyses of all cause and cancer mortality are currently underway.Cancer Incidence Among Patients Undergoing Cerebral Angiography with ThorotrastThe Branch recently completed a 40-year follow-up survey of site-specific cancer incidence after cerebral angiography with radioactive Thorotrast. The study population consisted of an international cohort of 3,042 patients injected during cerebral angiography with either Thorotrast or a non-radioactive agent. Compared with non-exposed patients, significantly elevated risks in Thorotrast patients were observed for all incident cancers combined, increased with time since angiography (P trend less than 0.001) and was 3-fold at 40 or more years; significant excesses (SIR = 4.0) persisted for 50 years. Increasing cumulative dose of radiation was associated with increasing risk of cancers of liver, gallbladder, and peritoneum and other digestive sites. A marginally significant dose-response was observed for pancreas cancer incidence (P = 0.05). After injection with greater than 20 ml Thorotrast, the cumulative excess risk of cancer incidence remained elevated for up to 50 years and approached 97%. Further analyses on Swedish patients compared with an unexposed control group of neurosurgical patients are in progress.